The standard synthesis for pyrazoles involves the reaction of a Beta-dicarbonyl compound with a hydrazine under mild conditions. See A. R. Katritzky in "The Principles of Heterocyclic Chemistry", Academic Press, New York (1968) at page 139. When the hydrazine is mono-substituted and the substituents attached to the two carbonyls of the .beta.-dicarbonyl compound are not equivalent, two isomeric products are possible. While the 1,5-diphenyl pyrazoles have excellent activity in alleviating inflammation and inhibiting the cyclooxygenase and/or lipoxygenase pathways of the arachidonic acid cascade, the 1,3-diphenyl pyrazoles do not show such excellent activity.
A synthetic scheme was developed whereby a high degree of regio-selectivity can be achieved in the preparation of 1,5-diarylpyrazoles. To minimize the product of the undesired isomer, the mono-substituted hydrazine was combined with a .beta.-dicarbonyl compound bearing an aliphatic or aromatic side chain containing a carboxylic acid moiety. This scheme is described in Murray, W., et al., Synthesis, 18-20 (January 1991) and U.S. Pat. No. 4,898,952.
Tepoxalin, 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]-N-hydroxy-N-methylp ropanamide, is a potent inhibitor of both the cyclooxygenase and lipoxygenase pathways of the arachidonic acid cascade. Wachter, M. et al, U.S. Pat. No. 4,826,868 (1989) and Robinson, C., Drugs of the Future, 15, 9, 202 (1990). One method of synthesizing tepoxalin, is disclosed in U.S. Pat. No. 4,898,952. This process uses methylene chloride and oxalyl chloride in the synthesis. Due to cost and toxicity considerations it is desirable to be able to synthesize tepoxalin without using methylene chloride or oxalyl chloride in the last step of the process. The removal of these reagents from the last step is more important than in earlier steps because earlier purifications and manipulations will dilute and remove traces of these compounds from the reaction stream before they reach the final product. If they are used in the last step, the final purification must remove all traces of these materials. The synthesis of structure II described in this invention obviates the need to use oxalyl chloride. The generation of structure II also eliminates the need to use methylene chloride in the last step replacing it with a less toxic alcoholic solvent.